Pharmacokinetics of erythropoietin in genetically anemic mice.
We examined the pharmacokinetics of recombinant human erythropoietin (rh-EPO) in genetically anemic mice (W/Wv genotype) to clarify its disposition mechanism in hematopoietic injury such as occurs in aplastic anemia. After rh-EPO was administered to W/Wv and control (+/+ genotype) mice once a day for 1 week at different doses, both the hematocrit (Hct) and tissue uptake clearance (CLup) of 125I-rh-EPO by spleen and bone marrow in the femur were estimated on the eighth day. The hematocrit increased on eighth day, depending on the dose administered. Compared with +/+ mice 10 times more rh-EPO was needed in W/Wv mice to produce an almost equivalent pharmacological effect. In +/+ mice, the CLup of 125I-rh-EPO by spleen increased to 4-fold that of controls after treatment with rh-EPO, 4.8 microg/kg, whereas that by bone marrow remained unchanged, irrespective of the dose administered. On the other hand, the increase in both the Hct and CLup in spleen was minimal in W/Wv mice. The CLup by bone marrow and spleen in both types of mice showed saturation with similar Km values (389-619 pM), comparable with the dissociation constant of the EPO receptor. In addition, the Hct correlated with the sum of the CLup by bone marrow and spleen in both types of mice, and the correlation lines were superimposable. These results suggest that the pharmacological receptors govern the saturable tissue uptake not only in normal mice but also in those that are anemic.
Kato
M
M
Drug metabolism and Pharmacokinetics Lab., Chugai Pharmaceutical Co., Ltd., Japan.
Miura
K
K
Kamiyama
H
H
Okazaki
A
A
Kumaki
K
K
Kato
Y
Y
Sugiyama
Y
Y
D000818:Animals; D001853:Bone Marrow / Q000378:metabolism; D004921:Erythropoietin / Q000097:blood / Q000493:pharmacokinetics* / Q000494:pharmacology; D005838:Genotype; D006400:Hematocrit; D007457:Iodine Radioisotopes / Q000378:metabolism; D007700:Kinetics; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D011994:Recombinant Proteins; D012044:Regression Analysis; D013154:Spleen / Q000378:metabolism
D007457:Iodine Radioisotopes; D011994:Recombinant Proteins; D004921:Erythropoietin